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Slow viral or prion diseases of the central nervous system

Slow viral or prion diseases of the central nervous system. Professor Sudheer Kher. Slow viral diseases of the central nervous system. tempo of clinical disease protracted incubation period (may also be protracted course of disease) multiple neurological symptoms.

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Slow viral or prion diseases of the central nervous system

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  1. Slow viral or prion diseases of the central nervous system Professor SudheerKher

  2. Slow viral diseases of the central nervous system • tempo of clinical disease • protracted incubation period • (may also be protracted course of disease) • multiple neurological symptoms

  3. Diseases caused by slow viruses • Creutzfeld-Jakob disease (CJD) • GSS- Gerstmann-Straussler-Scheinker syndrome • FFI- Fatal familial Insomnia • SSPE- SubacteSclerosing Pan Encephalitis • PML – Progressive Multifocal Leucoencephalopathy

  4. Kuru Fore tribe of New Guinea Predominant in women & children Progressive cerebellar ataxia and tremors Tribal practice of eating dead bodies of relatives after a “nonsterilising” ritual cooking No specific diagnosis or treatment

  5. SLOW INFECTIONS IN HUMANS • VIRUSES • SV40-like viruses (PML) • measles virus (SSPE) • rubella virus (PRP) PROGRESSIVE RUBELLA PANENCEPHALITIS • ATYPICAL AGENTS • Kuru, • Creutzfeld-Jakob disease (CJD) • (new) variant CJD disease (vCJD=nvCJD)

  6. Progressive multifocal leukoencephalopathy • Polyoma virus family, SV40-like (JC virus etc) • progressive, usually fatal, associated with immune suppression • HAART may prolong life in AIDS patients • but little effect on PML incidence • typically non inflammatory • but can get an inflammatory response in the brain after HAART treatment (immune reconstitution inflammatory syndrome) • demyelination (oligodendrocytes infected)

  7. SYMPTOMS • weakness • speech problems • cognitive problems • headaches • gait problems • visual problems • sensory loss • seizures http://library.med.utah.edu/WebPath/TUTORIAL/AIDS/AIDS076.html

  8. Progressive multifocal leukoencephalopathy • reactivation of latent infection • 70-80% population are seropositive • associated with immunosuppression • 1979: 1.5 per 10,000,000 population • 2004: 1 in 20 AIDS patients

  9. BK virus (polyoma) • Associated with urinary tract infections in immunosuppression • Possibly contributory factor in prostate cancer???

  10. MEASLES VIRUS • paramyxovirus family (morbillivirus genus) • sub-acute sclerosing panencephalitis • inflammatory disease • defective virus • ~1-10 yrs after initial infection • early infection with measles is a risk factor • rare complication of measles (7-70 cases per 1,000,000 cases measles) • vaccine protects against SSPE

  11. RUBELLA VIRUS • togavirus family (rubrivirus genus) • progressive rubella panencephalitis • inflammatory disease • years after initial infection • congenital / very early infections • very very rare

  12. Transmissible subacute spongiform encephalopathies Transmissible cerebral amyloidoses Prion diseases

  13. TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES (TSEs, TRANSMISSIBLE CEREBRAL AMYLOIDOSES, PRION DISEASES) • human • Kuru • Creutzfeldt-Jakob disease (CJD) • Gerstmann-Straussler-Scheinker syndrome (GSS) • fatal familial insomnia (FFI) • variant CJD (‘human BSE’) • animal • scrapie (sheep and goats) • bovine spongiform encephalopathy (BSE) Mad Cow Disease • transmissible mink encephalopathy • etc

  14. ATYPICAL AGENTS • atypical viruses • atypical agents • prions

  15. ATYPICAL AGENTS • SIMILAR TO VIRUSES • small • filterable • need host cells • no machinery for energy generation or protein synthesis • DIFFERENT FROM VIRUSES • no detectable virions in infected tissues • no detectable virions in purified infectious material • if nucleic acid is present, very small • very resistant to inactivation

  16. RESISTANT TO OR ONLY PARTIALLY INACTIVATED BY: • formaldehyde • ethanol • glutaraldehyde • ultraviolet and ionizing irradiation • non-ionic detergents • INACTIVATED BY: • autoclaving (121C for one hour) (> standard) • 5% sodium hypochlorite • sodium hydroxide • proteases, urea, other protein denaturants

  17. purified infectious material • protein present (PrP) • proteases inactivate • nucleic acid controversial • but little or none PRION

  18. PRION DISEASE • CNS • LONG INCUBATION • SLOW COURSE OF DISEASE (FATAL) • SPONGIFORM ENCEPHALOPATHY • VACUOLATION OF NEURONS • FIBRILLAR AGGREGATES, AMYLOID-TYPE MATERIAL (form plaques) • RARE IN MAN http://www.cdc.gov/ncidod/dvrd/cjd/ (Ermias Belay)

  19. Helical - Happy Beta-pleated sheet - Bad PRION PROTEIN (PrP)(host cell gene) PrP or PrPC alpha-helical protease sensitive PrPRES or PrPSC beta-pleated sheet protease resistant

  20. SCRAPIE • sheep • loss of muscular control • wasting • glial proliferation • vacuolation of neurons • amyloid plaques • abnormal properties infectious material • does not seem to cross sheep/human species barrier

  21. KURU • human disease • tremors, ataxia, weakness • dementia, death • amyloid plaques • spongiform changes • transmission – contact with infectious material

  22. CREUTZFELDT-JAKOB DISEASE • spongiform appearance of brain at autopsy • dementia, myoclonus, ataxia • 16-80+, usually 50-70 • Median age at death in US=68 yrs • 10% familial • also sporadic form • also acquired form (eg. iatrogenic CJD) • several hundred deaths in US per year

  23. CREUTZFELDT-JAKOB DISEASEclassical form • no evidence for direct person to person transmission • blood • milk • other body fluids • intimate social contact

  24. CREUTZFELDT-JAKOB DISEASE • iatrogenic CJD • human cadaver growth hormone • human cadaver gonadotropin • dural mater grafts • corneal transplantation • neurosurgical instruments • stereotactic EEG electrodes

  25. variant CJD (vCJD) • patients younger at presentation, more protracted course of disease • median age at death for UK vCJD patients=28 yrs • often patients present with psychiatric symptoms • BSE connection • seems bovine/human barrier is easier to cross than sheep/human barrier • distinctive pathological appearance • distinctive properties of the PrPres • agent is in some peripheral tissues • lymphoid tissues • 2 probable cases where transmitted by blood • future? • two cases in US – both had spent time in UK

  26. OTHER HUMAN PRION DISEASES • Gerstmann-Sträussler-Scheinker syndrome (GSS) (familial) • motor • sometimes regarded as subclass of CJD • fatal familial insomnia (FFI) • circadian rhythm problems • hypothalamus

  27. IMMUNE RESPONSE • no inflammatory response • no interferon induction • no antibody response • no cell-mediated response

  28. TREATMENT • invariably fatal • attempts at drug therapy disappointing • blood brain barrier

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